Abnormalities in the regulation of coagulation and thrombosis play a major role in the pathogenesis of many heart, lung, and blood diseases. This program project will integrate the research efforts of a number of independent investigators to explore the molecular basis for selected disorders of coagulation and thrombosis and the role of hemostatic balance in vascular disease pathogenesis. The PPG builds on the existing strength at the University of Michigan in human molecular genetics and cell and molecular biology of blood coagulation. The individual projects in this proposal emphasize the use of new technologies to provide improved biologic insight and develop new treatments for hemorrhage, thrombosis and related cardiovascular disorders. The 4 individual projects contained in this PPG will: 1) apply transgenic animal models to study factor V function in vivo; 2) explore the role of ER processing in coagulation FVIII and FV biosynthesis and identify the molecular basis for combined deficiency of factor V and factor VIII; 3) apply genetic models to study PAI-1 function in the vasculature and its role in the pathogenesis of atherosclerosis; and 4) study the regulation of fibrinolysis at sites of arterial injury. The PPG will support the development of 3 cores: A) the Mouse Coagulation Laboratory core; B) the DNA core; ; C) The PPG will aim to increase interaction and collaboration between individual project participants, as well as among the large number of other laboratories at the University of Michigan already engaged in research on coagulation, thrombosis and vascular disease. We anticipate that the overall program resulting from the combined efforts of all participants will significantly exceed the sum of individual parts.